This Komen-funded study is identifying and sending a letter of invitation to women with young-onset breast cancer and with their help to their parents. We will effectively combine their data with the DNA and environmental data now being collected from their unaffected sisters (who have joined the Sister Study) and DNA being collected from their parents. We will use this nuclear-family-based approach to study genetic and environmental factors involved in young-onset breast cancer. The study gains enormous operational efficiency advantages, by taking advantage of the infrastructure that is already in place and functioning smoothly for the Sister Study (Dale Sandler, PI). Mail-back saliva kits are providing DNA from cases and parents. We will collect clinical data and attempt to validate the diagnoses for all the anticipated 1,600 cases. Follow-up of these cases (through the Sister Study) will also allow us to identify environmental, clinical, and genetic factors that influence health after treatment. Case-parent analyses of gene variants are protected against bias due to confounding by genetic heritage, and also permit detection of both maternally-mediated genetic effects and parent-of-origin (imprinting) effects. In the proposed study, the participating affected sisters are each completing a computer-assisted telephone interview like the one their sister completed for the Sister Study, providing information about personal exposures, reproductive history, and past occupational exposures. Environmental effects will be identifiable through a paired comparison of affected and unaffected sisters. Gene-by-exposure interactions will be assessed with novel statistical methods. In summary, the proposed study leverages off the ongoing Sister Study to build a cost-effective, powerful, and statistically independent study of young-onset breast cancer. Findings related to combined effects of genetic variants and environmental factors can be replicated later in the Sister Study. We have now recruited a total of 1,517 breast cancer survivors, more than 1,000 of whom have completed all baseline activities. Some 900 are still pending, but we will need to end new enrollments of breast cancer survivor sisters at the end of September. We have also enrolled 1,292 of their parents, collecting 1,260 saliva samples from them. This work was accomplished with assistance from the EB support services contract. We have hired a postdoc, Chunyuan Fei, who will be writing papers based on the initial data set, using the case-control sibling sets based on the first 1,107 enrollees, who have provided questionnaire data that has been through the rigorous Westat quality control cleaning. This should provide good power for case-control analyses of environmental factors related to risk. Genotyping based on the available DNA is being deferred to provide time for recruitment of the parents into the study.